Derivatives of bis(-hydroxyaryl)alkanoic acids

ABSTRACT

This application relates to alcohols of the general formula   AND TO ACID ADDITION SALTS THEREOF. These substances inhibit cholesterol biosynthesis and aid in the regulation of cholesterol in the blood.

United States Patent 91 Fried et al.

[451 Feb. 27, 1973 DERIVATIVES OF 1318(- HYDROXYARYL)ALKANOIC ACIDS [75] Inventors: Josef Fried, Chicago, 111.; Edward J. Prlbyl, Metuchen, N.J.; John Krapcho, Somerset, both of NJ.

[73] Assignee: E. R. Squibb & Sons, Inc., New

York, NY.

[22] Filed: Sept. 30, 1970 [211 Appl. No.: 77,036

Related US. Application Data [63] Continuation-impart of Ser. No. 793,612, Jan. 23, 1969, abandoned, which is a continuation-in-part of Ser. No. 566,245, July 19, 1966, abandoned, which is a continuation-in-part of Ser. No. 288,630, June 18, 1963, abandoned.

[56] References Cited UNITED STATES PATENTS 2,220,834 1 l/ 1940 Bruson et al. ..260/293.64 3,449,418 6/1969 Werner et al. ..260/243 B 3,576,874 4/1971 Fried et al. ...260/243 B 3,455,918 7/1969 Marxer et al. ..260/326.5 G

Primary Examiner-Alex Maze] Assistant Examiner-R. J. Gallagher Attorney-Lawrence S. Levinson, Merle J. Smith [5 7] ABSTRACT This application relates to alcohols of the general formula R lower R R alkyl R lower A: lower Nalkylene-O 0alkylene-N 1 R 112),, R R R and to acid addition salts thereof. These substances inhibit cholesterol biosynthesis and aid in the regulation of cholesterol in the blood.

7 Claims, No Drawings DERIVATIVES OF 1318(- IIYDROXYARYL)ALKANOIC ACIDS This application is a continuation-in-part of application Ser. No. 793,612, filed Jan. 23, 1969 now abandoned, which in turn is a continuation-in-part of appli- 5 cation Ser. No. 566,245, filed July 19, 1966, now abandoned which is inturn a continuation-in-part of application Ser. No. 288,630, filed June 18, 1963, now abandoned.

SUMMARY OF THE INVENTION This invention relates to new compounds of the formula lower and to acid addition salts thereof.

The symbols in Formula I have the following meanings:

R represents hydrogen, lower alkyl, lower alkoxy or halo.

R represents or forms a heterocyclic group with the nitrogen.

n is l to 6.

The lower alkyl groups represented by the symbols referred to above include straight and branched chain saturated aliphatic groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl,

isoamyl, hexyl, and the like. Methyl and ethyl are 35 preferred. The lower alkoxy groups contain alkyl groups of the same character attached to an oxygen atom. Similarly, the lower alkylene groups are divalent radicals of the same kind.

Each of the four halogens is contemplated by the 40 term halo," but chlorine and bromine are preferred.

In the basic nitrogen containing radicals represented by each group The nitrogen may join with the groups represented by R to form a five to seven membered monocyclic 50 heterocyclic containing, if desired, an oxygen, sulfur or an additional nitrogen atom, (not more than two hetero atoms altogether), that is, the two symbols R represent together tetramethylene, pentamethylene, hexamethylene, oxapentamethylene, oxatetramethylene, 5

azahexamethylene, azatetramethylene, thiatetramethylene.

The radical II represents heterocyclic groups such as, for example, piperidino, (lower alkyl)piperidino, e.g., dimethylpiperidino, (lower alkoxy)piperidino, e.g., methoxypiperidino, pyrrolidino, (lower alkyl)pyrrolidino, e.g., methylpyrrolidino, di(lower alkyl)pyrrolidino, e.g., dimethylpyrrolidino, (lower alkoxy)pyrrolidino, e.g., ethoxypyrrolidino, morpholino, (lower alkyl)morpholino, e.g., Z-methylmorpholino, di(lower alkyl)morpholino, e.g., 2,3-dimethylmorpholino,

azapentamethylene, thiapentamethylene or (lower alkoxy)morpholino, e.g., ethoxymorpholino, thiamprpholino, (lower alkyl)thiamorpholino, e.g., 2- methylthiamorpholino, di(lower alkyl)thiamorpholino, e.g., 2,3-diethylthiamorpholino, 2,3- dimethylthiamorpholino, (lower alkoxy)thiamorpholino, e.g., 2-methoxythiamorpholino, piperazino, (lower alkyl)piperazino, e.g., N -methylpiperazino, Z-methylpiperazino or N-ethylpiperazino, di(lower alkyl)piperazino, e.g., 2,3-dimethylpiperazino, hydroxy-lower alkylpiperazino, e. g., hydroxyethylpiperazino, hexamethyleneimino and homopiperazino.

The new compounds of this invention may be 1 5 produced from esters of the formula III B lower R allkyl H O C- O l I wherein R is lower alkyl. These esters (III) are prepared by condensing the appropriate phenol with a 0 keto ester as described in J. Org. Chem. 23, 1004 R lower R R1 alkyl R lower 1 /N-alkylene0 (J O-alkylene-N\ R CH R it R OOR

Alternatively, the ester of Formula III can be reacted with a dihalide (hal-lower alkylene-hal) to form a halo alkylene ether which is reacted with an amine to form the ester of Formula V.

Hydrolysis of the compound of Formula V yields the corresponding acid (R=I-I).

Treatment of the ester or acid of Formula V with a reducing agent such as lithium aluminum hydride yields an alcohol of Formula I.

The bases of Formula 1 form acid addition salts by reaction with the common inorganic and organic acids. Such inorganic salts as the hydrohalides, e.g.,

hydrobromide, hydrochloride, hydroiodide, sulfates, nitrates, phosphates, borates, etc., and organic salts as acetate, oxalate, tartrate, malate, citrate, succinate, benzoate, pamoate, ascorbate, salicylate, theophyllinate, camphorsulfonate, alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g., benzenesulfonate, toluenesulfonate and the like are also within the scope of the invention. It is frequently convenient to effect the purification of the product by forming the acid salt. The base may be obtained therefrom by neutralization with an alkali hydroxide such as sodium hydroxide.

The new compounds of this invention are therapeutically active substances which are useful as hypocholesteremic agents. They inhibit cholesterol biosynthesis and regulate the cholesterol in the blood of warm-blooded animals such as rats and the like. Thus they are useful in the treatment of conditions such as atherosclerosis. These products may be administered orally or parenterally, e.g., at a dosage level of 2 to 40 mg./kg./day in single or divided doses, preferably 1 to 10 mg./kg. orally two to four times daily, in the form of tablets, capsules, elixirs, injectables, or the like by incorporating the base of Formula I or a physiologically acceptable acid addition salt thereof in a conventional vehicle prepared with suitable vehicle, excipient, lubricant flavor, etc., according to accepted pharmaceutical practice.

The following examples are illustrative of the invention. All temperatures are expressed on the Centigrade scale.

EXAMPLE 1 A. 4,4-Bis[p-(2-pyrrolidinoethoxy)phenyl]valeric acid, methyl ester A solution of 78.0g. (0.26 mole) of 4,4-bis(p-hydroxyphenyl)valeric acid, methyl ester in 250 ml. of dimethylformamide is treated portionwise with 26g. (0.54 mole) sodium hydride (50 percent dispersion). The reaction is exothermic and the temperature of the mixture is maintained below 60 by cooling. After completion of the addition of the hydride, the slurry is heated to 80, cooled to 40 and treated with 73g. (0.54 mole) of N-2-chloroethyl-pyrrolidine (released from the hydrochloride; b.p. 67/l2mm) (0.63 mole) in toluene. This mixture is gradually heated and then maintained at l-1l0 for 3 hours. The major portion of the solvent is removed under reduced pressure; the residue is treated with 200 ml. of water and then extracted twice with 600 ml. portions of ether. The ether phases are combined and shaken with (l) 100 ml. of 5 percent sodium bicarbonate solution and (2) 50 ml. of water. The ether phase is dried over magnesium sulfate, charcoal is added and the mixture filtered. The filtrate is concentrated under reduced pressure to give a syrupy material. A solution of the above material in 600 ml. of ether is added to a cold solution of 50 ml. of concentrated hydrochloric acid in 300 ml. of water. The mixture is shaken, the organic phase is discarded and the aqueous phase is washed with 300 ml. of ether. The aqueous phase is treated with a cold solution of 30g. of the sodium hydroxide in 100 ml. of water. The organic phase is extracted with 400 ml. portions of ether (three times). The ether phases are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a syrupy product.

B. 4,4-Bis[p-(2-pyrrolidinoethoxy )phenyl]pentanol The ester of Example 1A. (25g.) is dissolved in ether and added dropwise to an ethereal solution of 1.5g. of

lithium aluminum hydride. The mixture is refluxed for two hours, cooled and treated with a small quantity of sodium hydroxide solution. The ethereal solution of the product, 4,4-bix[p-(2-pyrrolidinoethoxy)phenyl]pentanol, is decanted from the inorganic salts, dried over magnesium sulfate, filtered and the solvent evaporated to give the product.

EXAMPLE 2 EXAMPLE 3 4,4-Bis[p-(2-morpholinoethoxy)phenyl]pentanol Interaction of 78g. of 4,4-bis(p-hydroxyphenyl)- valeric acid, methyl ester, with 26g. of 50 percent Nal-l and 82g. of 2-chloroethylmorpholine in dimethylformamide as described in Example 1A. gives 86.0g. of 4,4-bis[p-(2-morpholinoethoxy)phenyl]valeric acid, methyl ester. Treatment of this product according to the procedure of Example 1B. gives the pentanol.

EXAMPLE 4 4,4-Bis[p-[2-(2,6-dimethylmorpholino)ethoxy ]phenyl]pentanol Following the procedure of Example 1A., but substituting an equivalent quantity of 2-(2,6-dimethylmorpholino)ethyl chloride for the 2-diethylaminoethyl chloride, 4,4-bis[p-[2-(2,6-dimethylmorpholino)ethoxy1phenyllvaleric acid, methyl ester is obtained. Treatment of this product according to the procedure of Example 13. gives the pentanol.

EXAMPLE 5 4,4-Bis[p-[3-(4-methylpiperazino)propoxy1phenyl]pentanol Following the procedure of Example 1A., but substituting an equivalent amount of 3-(4-methylpiperazino)propyl bromide for the Z-diethylaminoethyl chloride, 4,4-bix[p-[3-(4-methylpiperazino)propoxy] phenyl1valeric acid, ethyl ester is obtained. Treatment of this produce according to the procedure of Example 15. gives the pentanol.

EXAMPLE 6 3,3-Bis[p-(2-pyrrolidinoethoxy)phenyl]butanol Following the procedure of Example lA. but substituting an equivalent quantity of 3,3-bis(p-hydroxyphenyl)butyric acid, ethyl ester for the 4,4-bis(phydroxyphenyl)valeric acid, ethyl ester, 3,3-bis[p-(2- pyrrolidinoethoxy)phenyl]-butyric acid, ethyl ester is obtained. Treatment of this product according to the procedure of Example 13. gives the butanol.

EXAMPLE 7 EXAMPLES 8-1 1 Using the procedure of Example 1A. but replacing the 4,4-bis(p-hydroxyphenyl)valeric acid, ethyl ester by the corresponding esters of A. 5,5-bis(3-methyl-4-hydroxyphenyl)-hexanoic acid,

B. 6 ,6-bis( 3-ethoxy-4-hydroxyphenyl )-heptanoic acid,

C. 7,7-bis(3-chloro-4-hydroxyphenyl)-octanoic acid,

D. 8,8-bis(3,5-dimethyl)-4-hydroxyphenyl nonanoic acid, respectively, there is obtained, respectively:

5,5-Bis[4-(2-pyrrolidinoethoxy)-3-methylphenyl ]hexanoic acid, ethyl ester.

6,6-Bis[4-(2-pyrrolidinoethoxyl)-3-ethoxyphenyl ]heptanoic acid, ethyl ester.

7,7-Bis[4-(2-pyrrolidinoethoxy)-3-chloropheny]octanoic acid, ethyl ester.

8,8-Bis[4-( 2-pyrrolidinoethoxy)-3 ,S-dimethylphenyl ]nonanoic acid, ethyl ester.

Treatment of each of the foregoing esters according to the procedure of Example 18. gives the following products:

Example 8, 5,5-Bis[4-(2-pyrrolidinoethoxy)-3- methylphenyl1hexanol.

Example 9, 6,6-Bis]4-(2-pyrrolidinoethoxy)-3 ethoxyphenyl1heptanol.

Example 10, 7,7-Bis[4-(2-pyrrolidinoethoxy)-3 chlorophenylloctanol.

Example 11, 8,8-Bis[4-(2-pyrrolidinoethoxy)-3,5- dimethylphenyflnonanol.

What is claimed is:

l. A compound of the formula R lower R R alkyl lower A: lower N-alkylene-O 0-alky1eneN R l 2) n H OH wherein R is hydrogen, lower aikyl having one to six carbons, lower alkoxy having one to six carbons, or halo; the two symbols R represent together tetramethylene, pentamethylene, hexamethylene, oxapentamethylene, oxatetramethylene, azahexamethylene, azapentamethylene, azatetramethylene, thiapentamethylene or thiatetramethylene, said groups being unsubstituted or substituted by methyl or methoxy; n is from 1 to 6, and acid addition salts thereof.

2. A compound according to claim 1 wherein each Rl N group is piperidino.

3. A compound according to claim 1 wherein each is piperazino.

4. A compound according to claim 1 wherein each is morpholino.

5. A compound according to claim 1 wherein each is pyrrolidino.

7. A compound according to claim 6 wherein each in N group is pyrrolidino, each R is hydrogen, each lower alkylene group has two carbon atoms, the lower alkyl group has one carbon atom and n is 2.

I l t 

2. A compound according to claim 1 wherein each group is piperidino.
 3. A compound according to claim 1 wherein each is piperazino.
 4. A compound according to claim 1 wherein each is morpholino.
 5. A compound according to claim 1 wherein each is thiamorpholino.
 6. A compound according to claim 1 wherein each is pyrrolidino.
 7. A compound according to claim 6 wherein each group is pyrrolidino, each R is hydrogen, each lower alkylene group has two carbon atoms, the lower alkyl group has one carbon atom and n is
 2. 